Melanoma incidence is increasing rapidly and is now the sixth most diagnosed cancer in the United States (Howlader, N. A., et al., SEER Cancer Statistics Review, 2014, pp 1975-2012, National Cancer Institute, Rockville, Md.). Although recent discoveries of genetic mutations (e.g., BRAFV600E) in melanoma have led to promising new therapies, the 5 year survival has improved marginally (<20%) because melanoma almost invariably develops resistance to these treatments (Howlader, N. A., et al., SEER Cancer Statistics Review, 2014, pp 1975-2012, National Cancer Institute, Rockville, Md.; Tseng, W. W., and Leong, S. P., Immunol. Lett. 2011, 139 (1-2), 117-118; Ackerman, A, et al., Cancer, 120 (11), 1695-1701; Sousa, R, et al., Int. J. Clin. Pract. 69(3), 273-280; and Tolk, H, et al., Melanoma Res. 25 (4), 362-366). Therefore, there is a critical need to develop new therapeutic options for patients suffering from this disease.
It is well-established that cancer cells, including metastatic melanoma, exhibit increased levels of oxidative phosphorylation (Murphy, M. P., Biochem. J. 2009, 417 (1), 1-13; Simons, A. L, et al., J. Cancer Res. Ther. 5 (9), 2-6; Aykin-Burns, N, et al., Biochem. J. 418 (1), 29-37; and Gius, D., and Spitz, D. R., Antioxid. Redox Signaling, 2006, 8 (7-8), 1249-1252). This increase in electron transport chain (ETC) activity results in elevated superoxide (O2⋅−) production and elevated levels of reactive oxygen species (ROS) (Ahmad, I. M, et al., J. Biol. Chem. 280 (6), 4254-4263; Lin, X, et al., Cancer Res. 63 (12), 3413-3417; and Spitz, D. R, et al., Ann. N. Y. Acad. Sci., 899, 349-62). It is believed that in nonmalignant cells, as many as 0.1% of the electrons that enter the ETC leak off and generate O2⋅−, which then reacts to form H2O2 and other organic hydroperoxides (ROOH). However, in cancer cells, the number of electrons that leak off the ETC and generate free radicals is significantly higher (Murphy, M. P., Biochem. J. 2009,417 (1), 1-13; Gius, D., and Spitz, D. R., Antioxid. Redox Signaling 2006, 8 (7-8), 1249-1252; Spitz, D. R, et al., Ann. N Y. Acad. Sci., 899, 349-62; Mueckler, M., Eur. J. Biochem., 1994, 219 (3), 713-725; and Adekola, K, et al., Curr. Opin. Oncol. 24 (6), 650-654). This results in chronic elevated levels of O2⋅−, ROS, and oxidative stress. In addition to increased levels of oxidative stress, the increase in electron leak leads to an increase in the mitochondrial membrane potential relative to nonmalignant cells (Simons, A. L, et al., J. Cancer Res. Ther. 5 (9), 2-6; Aykin-Burns, N, et al., Biochem. J. 418 (1), 29-37; and Gius, D., and Spitz, D. R., Antioxid. Redox Signaling 2006, 8 (7-8), 1249-1252). As a result, cancer cell mitochondria exhibit a large mitochondrial inner-membrane potential (150-180 mV), which is believed to be at least 60 mV greater than nonmalignant cells (Rohlena, J, et al., Antioxid. Redox Signaling 15 (12), 2951-2974; Murphy, M. P., Biochim. Biophys. Acta, Bioenerg., 2008, 1777 (7-8), 1028-1031; Murphy, M. P., and Smith, R. A., Annu. Rev. Pharmacol. Toxicol., 2007, 47, 629-656; Murphy, M. P., and Smith, R. A., Adv. Drug DeliveryRev., 2000, 41 (2), 235-250; Modica-Napolitano, J. S., and Aprille, J. R., Adv. Drug Delivery Rev., 2001, 49 (1-2), 63-70; Indran, I. R, et al., Biochim. Biophys. Acta, Bioenerg., 1807 (6), 735-745; and Chen, L. B., Annu. Rev. Cell Biol., 1988, 4, 155-181).
For these and other reasons there is a need for the present invention.